Role of the renal organic anion transporter OAT1 in metabolism and physiology
肾脏有机阴离子转运蛋白 OAT1 在代谢和生理学中的作用
基本信息
- 批准号:10408067
- 负责人:
- 金额:$ 46.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalATP-Binding Cassette TransportersAntibiotic TherapyAntibioticsAntioxidantsAttentionBindingBiochemical PathwayBiological AssayBody FluidsBranched-Chain Amino AcidsCCL21 geneCollectionComputational BiologyDataDiabetes MellitusDietDiet ModificationDiseaseDisease modelDockingDrug TransportEnsureFDA approvedFatty AcidsFatty acid glycerol estersFunctional disorderFutureGene ExpressionGuidelinesHigh Fat DietHumanIn VitroInsulin ResistanceInterferometryIntestinesKidneyKnock-outKnockout MiceLabelLigandsLiverMediatingMetabolicMetabolic DiseasesMetabolic PathwayMetabolic syndromeMetabolismMetabolite InteractionMethodsModelingMusNetwork-basedObesityOrganic Anion TransportersOrganoidsPathologicPathway AnalysisPathway interactionsPatientsPharmaceutical PreparationsPharmacologic SubstancePhysiologicalPhysiologyPlayPublishingRadiolabeledRegulationResearch PersonnelRoleSignaling MoleculeStudentsSubstrate SpecificityTechniquesTestingTimeTissuesValidationVitaminsbasedesigndietarygenome-widegut microbiomein silicoin vivoinduced pluripotent stem cellknockout animalmetabolomicsnovel therapeuticsreconstructionsuccesstranscriptomicsuptake
项目摘要
PROJECT SUMMARY/ABSTRACT
Owing to new regulatory guidelines, the organic anion transporter (OAT1)--a transporter discovered by the PI's
group (as NKT) and which is involved in the elimination of many common drugs--has received considerable
attention. But nearly all the published studies continue to focus on common drugs rather than endogenous
substrates of the transporter, which is highly conserved from an evolutionary standpoint. Metabolomics
analysis of our Oat1 knockout mice (Oat1KO), as well as in vitro transport data, indicate that OAT1 is a
major transporter of metabolites, signaling molecules, vitamins, gut microbiome products, and
antioxidants. Our previous genome-scale metabolic reconstructions of altered metabolism of the Oat1KO
mouse under normal dietary conditions enabled us to create the first multispecific "drug" transporter (OAT1)-
centered metabolic network--which was further supported by considerable metabolomics and in vitro data.
Many pathways (e.g., fatty acids, gut microbiome products, branched chain amino acids) in this largely
validated network of ~150-200 metabolites are also known to be important in metabolic diseases such as
diabetes, metabolic syndrome, obesity, and gut microbiome-associated illness. In this proposal: 1) We will use
dietary modifications (e.g., high fat, branched chain amino acids) and antibiotic treatment of the Oat1 KO mice
to define the role of Oat1 under conditions applicable to metabolic diseases. We will test the binding of
metabolites revealed by metabolomics under the various dietary conditions (or disease models) using a high
throughput unlabeled (BLI) assay to quantify the interaction of metabolites with OAT1; this information will be
used to prioritize metabolites for subsequent uptake assays involving the use of radiolabeled compounds. 2)
We will then use this information, together with gene expression data from the knockout tissues under various
dietary conditions, to reconstruct a metabolic network for each of these dietary (pathological model) conditions-
-using methods we have previously successfully used to create an "OAT1-centered metabolic network" under
normal dietary conditions. Together, these studies will help define the unique roles of OAT1 in regulation
of aberrant metabolism in these dysregulated metabolic states. Finally, we discuss how this information will
set the stage for understanding aspects of drug-induced metabolic syndrome in patients taking OAT1-
transported drugs. We have proven expertise in the necessary techniques and a team of world-class
collaborators to ensure success.
项目总结/摘要
由于新的监管指南,有机阴离子转运蛋白(OAT 1)--PI发现的转运蛋白
集团(如NKT),并参与消除许多常见药物-已收到相当大的
关注但几乎所有已发表的研究都继续关注普通药物,而不是内源性药物
转运蛋白的底物,从进化的角度来看高度保守。代谢组
对我们的Oat 1敲除小鼠(Oat 1 KO)的分析以及体外转运数据表明,OAT 1是一种
代谢物、信号分子、维生素、肠道微生物组产物的主要转运蛋白,以及
抗氧化剂我们之前对Oat 1 KO代谢改变的基因组规模代谢重建
正常饮食条件下的小鼠使我们能够创建第一个多特异性“药物”转运蛋白(OAT 1)-
中心的代谢网络-这是进一步支持了相当多的代谢组学和体外数据。
许多途径(例如,脂肪酸,肠道微生物组产物,支链氨基酸)在这很大程度上
还已知约150-200种代谢物的经验证的网络在代谢疾病中是重要的,
糖尿病、代谢综合征、肥胖和肠道微生物组相关疾病。在本建议中:1)我们将使用
饮食改变(例如,高脂肪、支链氨基酸)和抗生素治疗的Oat 1 KO小鼠
确定燕麦1在适用于代谢疾病的条件下的作用。我们将测试
代谢组学揭示的代谢物在各种饮食条件下(或疾病模型),使用高
通量未标记(BLI)试验,以定量代谢物与OAT 1的相互作用;该信息将
用于对代谢物进行优先级排序,以用于随后的摄取测定,包括使用放射性标记的化合物。(二)
然后,我们将使用这些信息,以及在各种条件下敲除组织的基因表达数据,
饮食条件,以重建这些饮食(病理模型)条件中的每一个的代谢网络-
- 使用我们以前成功用于创建“OAT 1为中心的代谢网络”的方法,
正常的饮食条件。总之,这些研究将有助于确定OAT 1在调控中的独特作用。
在这些失调的代谢状态下的异常代谢。最后,我们将讨论这些信息将如何
为了解服用OAT 1的患者中药物诱导的代谢综合征的各个方面奠定基础-
运输毒品。我们在必要的技术和世界一流的团队方面拥有成熟的专业知识,
合作伙伴,以确保成功。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SANJAY K NIGAM其他文献
SANJAY K NIGAM的其他文献
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{{ truncateString('SANJAY K NIGAM', 18)}}的其他基金
Role of the renal organic anion transporter OAT1 in metabolism and physiology
肾脏有机阴离子转运蛋白 OAT1 在代谢和生理学中的作用
- 批准号:
10179427 - 财政年份:2019
- 资助金额:
$ 46.72万 - 项目类别:
Role of the renal organic anion transporter OAT1 in metabolism and physiology
肾脏有机阴离子转运蛋白 OAT1 在代谢和生理学中的作用
- 批准号:
10645329 - 财政年份:2019
- 资助金额:
$ 46.72万 - 项目类别:
Role of the renal organic anion transporter OAT1 in metabolism and physiology
肾脏有机阴离子转运蛋白 OAT1 在代谢和生理学中的作用
- 批准号:
10224587 - 财政年份:2019
- 资助金额:
$ 46.72万 - 项目类别:
Role of the Perinatal Gut Microbiome in the Development of Adult Kidney Organic Anion Transport
围产期肠道微生物组在成人肾脏有机阴离子转运发展中的作用
- 批准号:
9763594 - 财政年份:2018
- 资助金额:
$ 46.72万 - 项目类别:
Structure Function Analysis of the Multi-specific Drug Transporter OCT1
多特异性药物转运蛋白OCT1的结构功能分析
- 批准号:
8814249 - 财政年份:2013
- 资助金额:
$ 46.72万 - 项目类别:
Structure Function Analysis of the Multi-specific Drug Transporter OCT1
多特异性药物转运蛋白OCT1的结构功能分析
- 批准号:
8422699 - 财政年份:2013
- 资助金额:
$ 46.72万 - 项目类别:
Structure Function Analysis of the Multi-specific Drug Transporter OCT1
多特异性药物转运蛋白OCT1的结构功能分析
- 批准号:
8666005 - 财政年份:2013
- 资助金额:
$ 46.72万 - 项目类别:
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